Steroid ketals



United States Patent i STEROID KETALS Barney J. Magerlein, Kalamazoo,and Robert H. Levin,

Kalamazoo Township, Kalamazoo County, Mich., assignors to The UpjohnCompany, Kalamazoo, Mich., a corporation of Michigan No Drawing.Application August 31, 1954, Serial No. 453,445

16 Claims. (Cl. 260-23955) The present invention relates to a new classof steroid ketals, the ll-ketosteroid ll-monoketals, and to a novelprocess for their production. i

It is an object of the present invention to provide the novelll-ketosteroid 11-monoketals and a novel process for their production. Afurther object is to provide 3,20-

dioxygenated-pregnane-ll-one ll-monoketals and a process for theirproduction. An additional object is to provide a carbonyl reagentderivative of thell-keto group in an ll-ketosteroid, which derivative isreadily isolated and purified and which is relatively non-reactive butcleavable to an ll-keto group when desired. Other ohsuch as cortisone orKendalls Compound F. For example, the 3,11,20-pregnanetrione ll-cyclicmonoketal can be converted to cortisone, with retention of an ll-cycliomonoketal group through as many steps as desired in order to facilitateisolation and purification of products,

in the same manner as 3,11,20-pregnanetrione is converted to cortisoneand other cortical hormones by prior art procedures [e. g. Mancera etal., J. Am. Chem. Soc., 74, 3711 (1952); Kritchevsky et a1., ibid., 74,483 (1952)]. Hydrolysis with strong acid converts the ll-cyclicmonoketal group to an ll-keto group at any desired step in thesynthesis. The 3,20-dihydroxyand 3,20-diacyloxypregnane-ll-one ll-cyclicmonoketals also can be converted to cortisone and other corticalhormones advantageously in the same manner. Other uses will be apparentto one skilled'in'the art.

Of the novel ll-ketosteroid ll-monoketals of themesent invention, thoseof particular interest are the 3,20- dioxygenated-pregnane-ll-onell-monoketals, especially the 3,20-dihydroxy-, 3,20-diketo-, and3,20-diacy1oxypregnane-l l-one ll-cyclic monoketals which may be repl.

resented by the structural formula:

and wherein R and R are selected from the group consisting of hydroxy,keto, andacyloxy of the Formula 2,771,46? Patented Nov. 20, 1956 ICCAcO, Ac being the acyl radical of a carboxylic acid, especially suchacids containing from one to eight carbon atoms, inclusive, illustrativeacids being formic, acetic, propionic, butyric, valeric, hexanoic,heptanoic, octanoic, succinic, cyclopentanoic, cyclohexanoic, benzoic,toluic, etc. with lower-aliphatic acids being preferred; and wherein R"is selected from the group consisting of hydrogen and lower-alkylradicals, illustratively methyl, ethyl, propyl, isopropyl, butyl,l-methylpropyl, amyl, hexyl, etc. and wherein n is an integer from oneto two. The 11- lower-alkylene glycol ketals, formed from1,2-alkanediols, are preferred.

According to the method of the present invention, an ll-monoketosteroidis reacted with a ketalizing agent in the presence of an acid catalystat a temperature between about twenty and about 200 degrees centigrade,to produce an ll-monoketosteroid' ll-monoketal. Hydroxysubstituted-ll-monoketosteroid ll-monoketals, e. g., 3,20-dihydroxypregnane-ll-one ll-cyclic monoketals, are converted toll-ketosteroid ll-monoketals containing additional keto groups, e. g.,3,11,20-pregnanetrione ll-cyclic monoketals by reaction with anoxidizing agent.

1 Many ll-monoketosteroids, the starting compounds for the ketalizationprocess of the present invention, are known. The particularlyinteresting 3,20- dihydroxyand 3,20-diacyloxypre'gnane-ll-ones, such as,for example, 3a,20-dihydroxypregnane-1l-one and 3a,20-diacetoxypregnane-ll-one, and related substituted pregnane-llones, can beprepared as described by Sarett [J. -Am. Chem. Soc., 71, 1175 (1949)].Other ll-monoketosteroids can be prepared by oxidation (e. g. withchromic acid) of ll-hydroxysteroids, which can be obtained, for example,by biooxidation (Murrayand Peterson, U. S. Patent 2,602,769).

Preferred ketalizing agents for the present process are thecyclic-ketal-forming ketalizing agents, particularly thealkane-1,2-diols and alkane-1,3-diols, illustratively, ethylene glycol,propane-1,2-diol, propane-1,3-diol, butane-'l,2-diol, pentane-l,2-diol,B-methylpentane-1,2-diol, hexane-1,3-diol, octane-1,2-diol,3-methyloctane-l,2-diol, decane-1,2-diol, etc. However other ketalizingagents, e. g; alcohols, illustratively ethanol, which form ketals thatare not cyclic, maybe employed if desired.

The acid catalyst used in the ketalization process of. the presentinvention is suitably a mineral acid or an organic sulfonic acid,normally only a trace amount being added, i. e. an amount below about 10percent by weight of the amount of starting steroid. Representativecatalysts are hydrochloric acid, sulfuric acid, metaandpara-toluenesulfonic acids, naphthalenesulfonic acid, benzenesulfonicacid, or ortho-chloro-benzenesulfonic acid, with paratoluenesulfonicacid being the preferred acid catalyst.

In carrying out the ketalization process of the present invention, thestarting ll-monoketosteroid is admixed,

the order of addition being unimportant, with at least the theoreticalamount of ketalizing-agent, preferably between about five and aboutfifty moles of ketalizing agent per mole of starting steroid, and atrace amount of acid catalyst, at a temperature between about twenty andabout 200 degrees centigrade, preferably between about fifty and aboutdegrees centigrade, for a reaction period of between about one hour andabout two weeks, preferably between about twelve hours and three daysthe length of time being dependent in part on the temperature,ketalizing agent, and catalyst employed. Normally the reaction isconducted using an organic solvent with which the reactants and productsare non-reactive, illustratively, benzene, toluene, xylene,nitrobenzene, methylene chloride, methylene dinitrobenzene, petroleumether, ether, nitrotoluene, etc., preferred solvents being those whichform an azeotrope with water, so that water can be re- 3, moved as it isformed in the course of the reaction when the temperature employed isabout the boiling point of the reaction mixture.

Oxidation of hydroxy groups in hydroxy-substituted-llmonoketosteroidll-monoketals to produce ll-ketosteroid ll-monoketals containingadditional keto groups is accomplished by using an oxidizing agent,illustratively potassium permanganate under neutral, basic, or mildlyacidic conditions, or chromic acid dissolved in acetic acid undersubstantially anhydrous conditions. In general strongly acidic reactionconditions are to be avoided, unless hydrolysis of the ll-ketal group toan ll-keto group is also desired.

The following examples illustrate the processes and products of thepresent invention but are not to be'construed as limiting.

Example 1.3a,20-dihydroxypregnane-Il-one 11-ethyl ene glycol ketal Amixture of 200 milligrams of 3a,20-dihydroxypregnane-ll-one, fivemilliliters of ethylene glycol, a trace of para-toluene-sulfonic acidmonohydrate (10 to 20 milligrams) and 100 milliliters of benzene wasplaced in a reaction flask which was equipped with a reflux condenserand a water trap so arranged that the condensed vapors passed throughthe water trap before returning to the reaction flask. The mixture washeated to reflux and was allowed to reflux for eighteen hours while, atthe same time, being agitated. The water which formed was removed byco-distillation with benzene and was collected in the water trap. Thereaction mixture was cooled, washed with a dilute solution of sodiumbicarbonate, and water, and dried. Removal of the solvent under reducedpressure yielded 222 milligrams of crude 30,20-dihYdI'OXY-pregnane-ll-one ll-ethylene glycol ketal melting at 205 to 215 degreescentigrade. Recrystallization from methanol gave pure3a,20-dihydroxypregnane-1l-one ll-ethylene glycol ketal melting at 241to 245 degrees centigrade.

Analysis.-Percent calculated for C2sH3sO4: C, 72.97; H, 10.12. Found: C,73.00; H, 10.22.

Example 2.3,11,20-pregnanetrine 1 I-ethylene glycol ketal Oxidation of3a,20-dihydroxypregnane-1l-one ll-ethylene glycol ketal from Example 1with chromic acid in acetic acid solution at room temperature yields3,11,20- pregnanetrione-l l-ethylene glycol ketal.

Hydrolysis of 3,11,20-pregnanetrione ll-ethylene glycol ketal withdilute sulfuric acid produces 3,11,20-pregnanetrione, melting point 158to 161 degrees centigrade. The isolation and purification of the3,11,20-pregnanetrione ll-ethylene glycol ketal is accomplished morereadily than with the parent 3,11,20-pregnanetrione.

Example 3 .-3p,ZO-dihydroxypregnane-I 1 -one 1 I-propane-1 ',2-diolketal In the same manner as given in Example 1, 33,20-dihydroxypregnane-l l-one 11-propane-1,2-diol ketal is preparedusing a mixture of 3 3,20-dihydroxypregnane-1l-one, propane-1,2-diol,para-toluenesulfonic acid monohydrate and benzene.

Example 4.3a,20-diacetoxypregnane-I1-one 11 -butane- 1 ',2-diol ketal3u,20-diacetoxypregnane-l l-one ll-butane 1',2'- diol ketal is preparedfrom 3u,20-diacetoxypregnane-1l-one in the same manner as given inExample 1 by using butane- 1, 2-diol instead of ethylene glycol as theketal forming agent and using sulfuric acid instead of para-toluenesul-'fonic acid as the catalyst. Hydrolysis of3a,20-diacetoxypregnane-ll-one 1l-butane-1',2-diol ketal using sodiumhydroxide dissolved in aqueous alcohol gives 3m,20-dihydroxypregnane-ll-one 11-butane-1,2-diol ketal.

Example 5 .3a,20-diacetoxypregnane-I I -one 11 -ethylene glycol ketal Inthe same manner as given in Example 1, 3u,20-diacetoxypregnane-ll-onell-ethylene glycol ketal is prepared from 3a,20-diacetoxypregnane-ll-oneby reaction with ethylene glycol in the presence of para-toluenesulfonicacid. 3u,20-diacetoxypregnane-1l-one ll-ethylene glycol ketal is readilyhydrolyzed with aqueous potassium hydroxide using ethyl alcohol as asolvent to produce 3a,20-dihydroxypregnane-1l-one ll-ethylene glycolketal which melts at 242-245 degrees centigrade and is identical withthe product of Example 1. This high-melting 11- ketal compound is morereadily isolated and purified than the lower melting parent3a,20-dihydroxypregnane-11- one; melting point 217 to 220 degreescentigrade.

Example 6.11-/cetoeti0ch0lane II-ethylene glycol ketalll-ketoetiocholane [Reichstein, Ergeb. Vitamin-Hormonforsch, 1, 352(1938)] when heated with an excess of ethylene glycol and a trace ofpara-toluenesulfonic acid monohydrate using benzene as the solvent,following the method of Example 1, gives ll-ketoetiocholane ll-ethyleneglycol ketal.

Example 7 .3 (1,1 7 a-dihydroxyctioch0lane-1 1 -one II-ethylene glycolketal In the same manner as shown in Example 6,3a,17adihydroxyetiocholane-ll-one is converted to3a,17a-dihydroxyetiocholane-ll-one ll-ethylene glycol ketal.

Example 8.31x,1 7a-dihydroxyeti0cholane-I I-one 3,1 7-

diacetate 1 I -ethylene glycol ketal Using3a,17ot-dihydroxyetiocholane-1l-one 3,17-diacetate in place of thell-ketoetiocholane in Example 6 pro duces3a,17a-dihydroxyetiocholane-1l-one 3,17-diacetate ll-ethylene glycolketal. Hydrolysis of this thus-produced ll-ethylene glycol ketal withpotassium hydroxide in aqueous methanol solution yields3a,17a-dihydroxyetiocholane-l l-one ll-ethylene glycol ketal which isidentical with the product of Example 7.

Example 9.-3a,20-dipropionoxypregnane-I 1 -one I 1 -propane-1',3'-diolketal Using the procedure of Example 1,3a,20-dipropionoxypregnane-ll-one l1-propane-1',3-diol ketal is preparedfrom 3a,20-dipropionoxypregnane-1l-one by using propane-1,3-diol inplace of ethylene glycol. Hydrolysis of 3d,20-dipropionoxypregnane-1l-one 1 1-propane-1,3'-diol ketal using dilute sulfuric acid yields3u,20-dihydroxyprgnane-ll-one, melting point 217-219 degrees centigrade.

Example 1 0.-3 u,1 7a-dihydroxyetiocholane-I1-one 3-benzoate 1 7-acetate1 I -ethylene glycol ketal 3a, 17ot-dihydroxyetiocholane-1l-one3-benzoate 17- acetate used in place of ll-ketoetiocholane in the methodof Example 6, provides 3a,l7a-dihydroxyetiocholane-1lone 3-benzoate17-acetate ll-ethylene glycol ketal. Hydrolysis of the thus-producedll-ketal with dilute sulfuric acid yields3a,17a-dihydroxyetiocholane-1l-one, melting at 253-255 degreescentigrade, a compound less readily isolated and purified than the3a,17a-dihydroxyetiocholane-l l-one ll-ethylene glycol ketal obtained inExample 7.

It is to be understood that the invention is not to be limited to theexact details of operation or exact compounds shown and described, asobvious modifications and equivalents will be apparent to one skilled inthe art and the invention is therefore to be limited only by the scopeof the appended claims.

r We claim: "1. 3,20-dioxygenated-pregnane-1l one ll-cyclic monoketalhaving the formula wherein R and R are selected from the groupconsisting of hydroxy, keto, and acyloxy of the formula AcO, Ac beingthe acyl radical of a hydrocarbon carboxylic acid containing from one toeight carbon atoms, inclusive; and wherein R" is selected from the groupconsisting of hydrogen and lower-alkyl radicals containing from one tosix carbon atoms, inclusive; and wherein n is an integer from one totwo, inclusive.

2. 3,20-dihydroxypregnane-ll-one ll-cycli-c monoketal having the formula11-propane-1',2-

r C=O (0 H2) n-o wherein R is selected from the group consisting ofhydrogen and lower-alkyl radicals containing from one to six carbonatoms, inclusive; and wherein n is an integer from one to two inclusive.

6. 3,11,20-pregnanetrione ll-ethylene glycol ketal.

7. 3,20-diacy-loxypregnane-1l-one ll-cyclic monoketal having the formulawherein AcC) is acyloxy, Ac being the acylrad icai of a hydrocarboncarboxylic acid containing from one to eight carbon atomsinclusive; andwherein R is selected from the group consisting of hydrogen andlower-alkyl radicals containing from one to six'carbon atoms inclusive;and wherein n is an integer from one to two, inclusive.

8. 3a,20-diacetoxypregnane-1l-one ll-ethylene glycol ketal. P9. In aprocess for the production of 3,20-dioxygenatedpregnane-11-one 1l-cyclicmonoketal having the formula wherein Rand R are selected from the groupconsisting of hydroxy, keto, and acyloxy of the formula AcO, Ac beingthe acyl radical of a carboxylic acid containing from one to eightcarbon atoms inclusive; and wherein R" is selected from the groupconsisting of hydrogen and alkyl; and wherein n is an integer from oneto two, inclusive, the step which comprises reacting ll-ketosteroid ofthe formula wherein R and R are selected from the group consisting ofhydroxy and acyloxy of the formula AcO, Ac being the acyl radical of acarboxylic acid containing from one to eight carbon atoms inclusive,with a ketalizing agent selected from the group consisting ofalkane-1,2-diol-s and alkane-1,3-diols in the presence of an acidcatalyst and an organic solvent at a temperature between about fifty andabout degrees centigrade to produce 11- keto'steroid ll-cyclicmonoketal.

10. A process which comprises reacting 3,20-dihydroxypregnane-ll-onewith an excess of ketalizing agent selected from the group consisting ofalkane-1,2-diols and a1kane1,3-diols containing from two to eight carbonatoms, inclusive, in the presence of an acid catalyst and an organicsolvent which forms an azeotrope with water, at a temperature about theboiling point of the mixture; removing Water as formed in the course ofthe reaction; and separating thus-produced 3,20-dihydroxypregnane-11-one ll-cyclic monoketal.

11. A process which comprises reacting 3a,20-dihydroxypregnane-ll-onewith an excess of ethylene glycol in the presence of a trace amount ofacid catalyst, and an organic solvent which forms an azeotrope withwater, at a temperature about the boiling point of the mixture;

removing water as formed in the course of the reaction;

and separating thus-produced 3u,20-dihydroxypregnanell-one ll-ethyleneglycol ketal.

12. A process which comprises reacting 3a,20-dihydroxypregnane-ll-onewith an excess of propane-1,2-diol in the presence of a trace amount ofacid catalyst, and an organic solvent which forms an azeotrope withwater, at a temperature about the boiling point of the mixture; removingwater as formed in the course of the reaction;

7 and separating thus-produced 3a,20-dihydroxypregnanell one11-propane-1',2-dio1 ketal.

13. A process which comprises reacting 3,20-dihydroxypregnane-ll-onewith an excess of ketalizing agent Selected from the group consisting ofalkane-1,2-diols and alkane-1,3-diols containing from two to eightcarbon atoms, inclusive, in the presence of an acid catalyst and anorganic solvent which forms an azeotrope with water, at a temperatureabout the boiling point of the mixture; removing water as formed in thecourse of the reaction; oxidizing resulting3,20-dihydroxypregnane-ll-one 11- cyclic monoketal with an oxidizingagent under conditions other than strongly acidic conditions; andseparating thus-produced 3,11,20 pregnanetrione 11 cyclic monoketal.

14. A process which comprises reacting 3a,20-dihydroxypregnane-ll-onewith an excess of ethylene glycol in the presence of a trace amount ofacid catalyst, and an organic solvent which forms an azeotrope withwater, at a temperature about the boiling point of the resultingmixture; removing water as formed in the course of the reaction;separating resulting 3a,20-dihydroxypregnanell-one ll-ethylene glycolketal; oxidizing 30,20-dihY- droxypregnane-ll-one ll-ethylene glycolketal with an oxidizing agent under conditions other than stronglyacidic conditions; and separating thus-produced 3,11,20- pregnanetrionell-ethylene glycol ketal.

15. A process which comprises reacting 3,20-diacy1oxypregnane-ll-one,wherein acyloxy is of the formula AcO, Ac being the acyl radical of acarboxylic acid containing from one to eight carbon atoms, inclusive,with an excess of ketalizing agent selected from the group consisting ofalkane-1,2-diols and alkane-1,3-diols containing from two to eightcarbon atoms, inclusive, in the presence of an acid catalyst and anorganic solvent which forms an azeotrope with water, at a temperatureabout the boiling point of the mixture; removing water as formed in thecourse of the reaction; and separating thus-produced3,20-diacyloxypregnane-1l-one ll-cyclic monoketal.

16. A process which comprises reacting 3u,20-diacetoxypregnane-ll-onewith an excess of ethylene glycol in the presence of a trace amount ofacid catalyst, and an organic solvent which forms an azeotrope withwater, at a temperature about the boiling point of the mixture; removingwater as formed in the course of the reaction; and separatingthus-produced 3a,20-diacetoxypregnane-ll-one ll-ethylene glycol ketal.

References Cited in the file of this patent UNITED STATES PATENTS2,288,854 Stavely July 7, 1942 2,352,568 Reichstein June 27, 19442,378,918 Fernholz June 26, 1945

1. 3,20-DIOXYGENATED-PREGNANE-11-ONE 11-CYCLIC MONOKETAL HAVING THEFORMULA